PROJECT SUMMARY Although the single most significant risk factor for developing Alzheimer's disease (AD) is age, the neurobiological processes underlying the transition from normal aging to AD are not well understood. The loss of white matter (WM) integrity is known to occur in normal aging and it is hypothesized that an accelerated loss of WM integrity is one mechanism for the transition from normal aging to AD. Indeed, the age-related loss of WM integrity in late-myelinating association regions in the frontal and temporal lobes are the same neocortical regions most vulnerable to the development of AD pathology. In direct response to announcement PAR-15-357: Understanding Alzheimer's Disease in the Context of Brain Aging, we propose to investigate the hypothesis that changes in brain WM integrity are key mechanisms by which a normal aging brain can transition to AD. Our group has recently developed MRI-based biomarkers that are sensitive to subtle changes in WM integrity. These biomarkers consist of quantitative WM tract integrity (WMTI) metrics that characterize specific tissue properties such as axonal density and myelin integrity. Using these WMTI metrics, we have differentiated normal controls from patients with MCI, indicating that WM changes occur early in the AD disease process. We have also demonstrated that these WMTI metrics may be useful even earlier in the process by differentiating between normal controls with and without hippocampal atrophy. Thus, the overall hypothesis of this project is that an accelerated loss of WM integrity is evident in the transition from normal aging to AD, and by combining biomarkers of WMTI, degree of A? accumulation, neurodegeneration (i.e. hippocampal and cortical atrophy), and cognitive function, we will be able to stratify cognitively intact older adults for risk of conversion to MCI/AD.